Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway.
Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway.
复制标题
DOI：
10.1371/journal.pone.0078284
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Su D
中科院分区：
文献类型：
--
作者：
Jia L;Xing J;Ding Y;Shen Y;Shi X;Ren W;Wan M;Guo J;Zheng S;Liu Y;Liang X;Su D
越来越多的临床证据表明，高尿酸血症与2型糖尿病的风险增加有关。然而，目前尚不清楚尿酸水平升高是否会导致胰腺β细胞的直接损伤。在这项研究中，我们研究了尿酸对β细胞活力和功能的影响。每天腹腔注射尿酸溶液或生理盐水，持续4周。尿酸处理的小鼠表现出显着受损的葡萄糖耐量和较低的胰岛素水平在葡萄糖的挑战比对照组小鼠。然而，两组之间的胰岛素敏感性没有显著差异。与对照小鼠的胰岛相比，尿酸处理小鼠的胰岛尺寸明显较小，含有较少的胰岛素。尿酸处理体外培养的胰岛β细胞可通过IκBα磷酸化激活NF-κB信号通路，导致诱导型一氧化氮合酶（iNOS）表达上调和一氧化氮（NO）产生过量。尿酸处理也增加了Min 6细胞的凋亡和下调Bcl-2的表达。此外，在尿酸处理的小鼠胰岛中观察到葡萄糖刺激下胰岛素分泌减少。尿酸转运蛋白抑制剂苯溴马隆、NOS抑制剂L-NMMA和NF-κB抑制剂Bay 11-7082可减轻尿酸对胰岛β细胞的这些有害作用。进一步的研究表明，尿酸通过促进MafA蛋白的降解来抑制MafA蛋白的水平。总的来说，我们的数据表明，尿酸水平升高通过NF-κB-iNOS-NO信号转导轴引起β细胞损伤。
Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid–treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid–treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11–7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.
登录
查看更多内容
DOI：
10.1152/ajprenal.00104.2006
发表时间：
2007-01-01
影响因子：
4.2
作者：
Han, Ho Jae;Lim, Min Jin;Taub, Mary
通讯作者：
Taub, Mary
影响因子：
4.5
作者：
Conen D;Wietlisbach V;Bovet P;Shamlaye C;Riesen W;Paccaud F;Burnier M
通讯作者：
Burnier M
影响因子：
5.1
作者：
Nan, Hairong;Qiao, Qing;Tuomilehto, Jaakko
通讯作者：
Tuomilehto, Jaakko
影响因子：
4.1
作者：
HEDESKOV, CJ;CAPITO, K
通讯作者：
CAPITO, K
DOI：
10.1073/pnas.90.19.8992
发表时间：
1993-10-01
影响因子：
11.1
作者：
CORBETT, JA;MIKHAEL, A;UNANUE, ER
通讯作者：
UNANUE, ER